USE PE DERIVATIVES OF PYRIMIDILAMINOBENZAMIDA PUU- THE TREATMENT OF SYSTEMIC MASTOCYTOSIS
Brief Description of the Invention The present invention relates to the use of pyrimidylaminobenzamide derivatives for the preparation of a drug for the treatment of systemic mastocytosis. The present invention also relates to a method for treating systemic mastocytosis. BACKGROUND OF THE INVENTION Systemic mastocytosis (SM) can be classified into indolent MS (with little or no evidence of impaired organ function), aggressive SM (presence of impaired organ function), hematologic non-mast cell disease associated with MS (SM -AHNM D) and mast cell cell leukemia. Clinical presentation in adult MS is heterogeneous and includes skin disease (usually urticaria pigmentosa), symptoms of mast cell mediator release (headache, flow, light-headedness, syncope, anaphylaxis, etc.), and damage Direct or indirect to organs (bone pain from lytic bone lesions, osteoporosis or bone fractures, hepatosplenomegaly, cytopenia of involvement of bone marrow). In addition, approximately 20% of patients with MS may exhibit significant and sometimes isolated blood eosinophilia (Tefferi and Pardanani 2004). In general, mast cell cell leukemia is a terminal disease with survival measured in months and there is no effective therapy to date. The natural history of indolent MS is much better with average survival measured in decades and infrequent progress to SM and SM-AHN M D aggressive. In SM whether indolent or aggressive without AHNM D, the elevated content of mast cells of bone marrow and eosinophils, elevated serum alkaline phosphatase, anemia and hepatosplenomegaly have been associated with poor prognosis (Tefferi and Pardanani 2004). Complete histological and clinical remission has been achieved in patients with MS associated with the fusion of the FIP1 L1 -PDGFRa gene when treated with Gleevec® (Pardanani 2003a, Pardanani 2003b). It has now been found that pyrimidylaminobenzamide derivatives are effective against MS, especially SM associated with fusion of the FIP1 L1 -PDGFRa gene. The problem to be solved by the present invention is that of the pyrimidylaminobenzamide derivatives which are useful in the treatment of especially systemic mastocytosis, especially MS associated with the fusion of the FI P1 L 1 -PDG FRa gene. Brief Description of the Invention The present invention relates to the use of pyrimidylaminobenzamide compounds of the formula (I) (hereinafter: "DERIVATIVES DE PI RI MY DI LAM I NOBENZAM I DA"): wherein: Ri represents hydrogen, alkyl Bottom, lower alkoxy-lower alkyl, lower acyloxyalkyl, lower carboxyalkyl, lower alkoxy-carbonylalkyl-lower or phenylalkyl-lower; R2 represents hydrogen, lower alkyl, optionally substituted by one or more identical or different R3 radicals, cycloalkyl, bencycloalkyl, heterocyclyl, an aryl group, or a mono- or bicyclic heteroaryl group comprising zero, one, two or three nitrogen atoms in the ring and zero or one atom of oxygen and zero or one atom of sulfur, such groups in each case are unsubstituted or mono- or polysubstituted; And R3 represents hydroxy, lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, carbamoyl N-mono- or N .N-disubstituted, amino, mono- or disubstituted amino, cycloalkyl, heterocyclyl, an aryl group, or a mono- or bicyclic heteroaryl group comprising zero, one, two or three nitrogen atoms in the ring and zero or one oxygen atom and zero or one sulfur atom, such groups in each case are unsubstituted or mono- or polysubstituted; or wherein R and R2 together represent alkylene with four, five or six carbon atoms optionally mono- or disubstituted by lower alkyl, cycloalkyl, heterocyclyl, phenyl, hydroxy, lower alkoxy, amino, mono- or disubstituted amino, or? o, pyridyl, pyrazinyl or pyrimidinyl; benzalkylene with four or five carbon atoms; oxaalkylene with one oxygen and three or four carbon atoms; azaalkylene with a nitrogen and three or four carbon atoms wherein the nitrogen is unsubstituted or substituted by lower alkyl, phenyl to lower quary, lower alkoxycarbon and lower alkyl, carboxy-lower alkyl , carbamoylalkyl-lower, carbamoylalkyl-lower N-mono- or N, N-disubstituted, cycloalkyl, lower alkoxycarbonyl, carboxy, phenyl, substituted phenyl, pyridinyl, pyrimidinyl or pyrazinyl; R 4 represents hydrogen, lower alkyl or halogen; and an N-oxide or a pharmaceutically acceptable salt of such compound for the preparation of a pharmaceutical composition for the treatment of systemic mastocytosis and SM associated with fusion of the FI P1 L 1 -PDGFRα gene. The present invention also relates to the use of compounds of the formula I to treat or prevent systemic mastocytosis. The general terms used before and after in the present preferably have, within the context of this description, the following meanings, unless otherwise indicated: The prefix "lower" indicates a radical having up to and including a maximum of 7, especially up to and including a maximum of four carbon atoms, the radicals in question that are either linear or branched with single or multiple branching. When the plural form is used for the compounds, salts and the like, it is also taken to mean a single compound, salt or the like. Any asymmetric carbon atoms can be present in the (R) -, (S) - or (R, S) - configuration, preferably in the (R) - or (S) configuration. The compounds can then be present as mixtures of isomers or as pure isomers, preferably as diastereomers of pure enantiomers. The invention also relates to the possible tautomers of the compounds of the formula I. The lower alkyl is preferably alkyl with from and including 1 to and including 7, preferably from and including 1 to and including 4, and is linear or branched; preferably lower alkyl is butyl, such as n-butyl, sec-butyl, isobutyl, tert-butyl, propyl, such as n-propyl or isopropyl, ethyl or methyl. Preferably, lower alkyl is methyl, propyl or tert-butyl. Lower acyl is preferably formyl or lower alkylcarbonyl, in particular acetyl. An aryl group is an aromatic radical that is linked to the molecule by a bond located on a carbon atom of the aromatic ring of the radical. In a preferred embodiment, aryl is an aromatic radical having from 6 to 14 carbon atoms, especially phenyl, naphthyl, tetrahydronaphthyl, fluorenyl or phenanthrenyl, and is unsubstituted or substituted by one or more, preferably up to three, especially one or more substituents, especially selected from amino, mono- or disubstituted amine, halogen, lower alkyl, substituted lower alkyl, lower alkenyl, lower alkynyl, phenyl, hydroxy, etherified or esterified hydroxy, nitro, cyano, carboxy, esterified carboxy, alkanoyl, benzoyl, carbamoyl, carbamoyl N-mono- or N, N-disubstituted, amidino, guanidino, ureido, mercapto, sulfo, lower alkylthio, phenylthio, phenylalkylthio, lower alkyl or rf eni 11, lower alkylsulfinyl, phenylsulfinyl, phenylalkyl -lower-sulfinyl, lower-alkyl-phenylsulfinyl, lower-alkyl-sulfonyl, phenylsulphonyl, phenylalkyl-lower-sulfonyl, lower alkylsulfonyl, halogen-alkyl n-mercapto, such as, especially, trifluoromethanesulfonyl, dihydroxy (-B (OH) 2), heterocyclyl, a mono- or bicyclic heteroaryl group and lower dioxy-alkylene linked to adjacent carbon atoms of the ring, such as dioxymethylene. Aryl is more preferably phenyl, naphthyl or tetrahydronaphthyl, which in any case is unsubstituted or independently substituted by one or two substituents selected from the group comprising halogen, especially fluorine, chlorine or bromine; hydroxy; hydroxy etherified by lower alkyl, for example by methyl, by halogen-lower alkyl, for example trifluoromethyl, or by phenyl; lower dioxyalkylene bonded to two adjacent carbon atoms, for example methylenedium? i, lower alkyl, for example methyl or propyl; halogen-lower alkyl, for example trifluoromethyl; lower hydroxyalkyl, for example hydroxymethyl or 2-hydroxy-2-propyl; lower alkoxy-lower alkyl, for example methoxymethyl or 2-methoxymethyl; lower alkoxycarbonyl-lower alkyl, for example methoxycarbonylmethyl; lower alkynyl, such as 1-propynyl; esterified carboxy, especially lower alkoxycarbonyl, for example methoxycarbonyl, n-propoxycarbonyl or isopropoxycarbonyl; N-mono-substituted carbamoyl, in particular carbamoyl monosubstituted by lower alkyl, for example methyl, n-propyl or isopropyl; Not me; alkyl-lower-amino, for example methylamino; dialkyl-lower-amino, for example dimethylamino or diethylamino; alkylene-lower-amino, for example pyrrolidino or piperidino; oxaalkylene-lower-amino, for example morpholino, azaalkylene-lower-amino, for example piperazino, acylamino, for example acetylamino or benzoylamino; alkyl-lower sulfonyl, for example methylsulfonyl; sulfamoyl; or phenylsulfonyl. A cycloalkyl group is preferably cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl, and can be unsubstituted or substituted by one or more, especially one or two, substituents selected from the group defined above as substituents for aryl, glutamic, more preferably by lower alkyl, such as methyl, lower alkoxy, such as methoxy or ethoxy, or hydroxy, and furthermore by oxo or fused to a venzo ring, such as in benzcyclopentyl or benzcyclohexyl. Alkyl substituted is alkyl as defined at the end, especially lower alkyl, preferably methyl; where one or more, especially up to three, substituents may be present, mainly from the selected halogen group, especially fluorine, amino, N-lower alkyl-amino, N, N-dialkyl-lower-amino, N-lower alkyl- amino, hydroxy, cyano, carboxy, lower alkoxycarbonyl, and phenylalkoxy-lower carbonyl. Trifluoromethyl is especially preferred. Amino mono- or disubstituted amino is especially amino substituted by one or two radicals independently selected from each other of lower alkyl, such as methyl; hydroxyalkyl-lower, such as 2-hydroxyethyl; lower alkoxy-lower alkyl, such as methoxyethyl; phenylalkyl-lower, such as benzyl or 2-phenylethyl; lower alkanoyl, such as acetyl; benzoyl; substituted benzoyl, wherein the phenyl radical is especially substituted by one or more, preferably one or two, substituents selected from nitro, amino, halogen, N-lower-alkyl-amino, N, N-dialkyl-lower-amino, hydroxy , cyano, carboxy, lower alkoxycarbonyl, lower alkanoyl, and carbamoyl; and phenylalkoxy-lower carbonyl, wherein the phenyl radical is unsubstituted or substituted especially by one or more, preferably one or two, substituents selected from nitro, amino, halogen, N-lower alkyl-amino, N. dialkyl-lower-amino, hydroxy, cyano, carboxy, lower alkoxycarbonyl, lower alkanoyl and carbamoyl; and preferably it is N-lower alkyl-amino, such as N-methylamino, hydroxyalkyl-lower-amino, such as 2-hydroxyethylamino or 2-hydroxypropyl, lower alkoxy-lower alkyl, such as methylene glycol, phenylalkyl- lower-amino, such as benzylamino, N, N-dialkyl-lower-amino, N-phenylalkyl-lower-N-lower alkyl-amino, N, N-dialkyl-lower-phenylamino, lower alkanoyl-amino, such as acetylamino, or a substituent selected from the group comprising benzoylamino and phenylalkoxy-lower-carbonylamino, wherein the phenyl radical in each case is unsubstituted or substituted especially by nitro or amino, or also by halogen, amino, N-lower alkyl-amino , N, N-dialkyl-lower-amino, hydroxy, cyano, carboxy, lower alkoxycarbonyl, lower alkanoyl, carbamoyl or aminocarbonylamino. The disubstituted amino is also alkylene-lower-amino, for example pyrrolidino, 2-oxopyrrolidino or piperidino; oxaalkylene-lower-amino, for example morpholino, or azaalkylene-lower-amino, for example piperazino or N-substituted piperazino, such as N-methylpiperazino or N-methoxycarbonylpiperazino. Today halogen is especially fluorine, chlorine, bromine or iodine, especially fluorine, chlorine or bromine. The etherified hydroxy is especially alkyloxy of 8 to 20 carbon atoms, such as n-decyloxy, lower alkoxy (preferred), such as methoxy, ethoxy, isopropyloxy, or tert-butyloxy, phenylalkoxy-lower, such as benzyloxy, phenyloxy, halogen -alkoxy-lower, such as trifluoromethoxy, 2,2,2-trifluoroethoxy or 1,1, 2,2-tetrafluoroethoxy, or lower alkoxy which is substituted by mono- or bicyclic heteroaryl comprising one or two nitrogen atoms, lower alkoxy preference which is substituted by imidazolyl, such as 1 H-imidazol-1-yl, pyrrolyl, benzimidazolyl, such as 1-benzimidazolyl, pyridyl, especially 2-, 3- or 4-pyridyl, pyrimidinyl, especially 2-pyrimidinyl , pyrazinyl, isoquinolinyl, especially 3-isoquinolinyl, indolyl or thiazolyl. The esterified hydroxy is especially lower alkanoyloxy, benzoyloxy, lower alkoxycarbonyloxy, such as tert-butoxycarbonyloxy, or phenylalkoxy-lower-carbonyloxy, such as benzyloxycarbonyloxy. The esterified carboxy is especially lower alkoxycarbonyl, such as tert-butoxycarbonyl, isopropylcarbonyl, methoxycarbonyl or ethoxycarbonyl, phenylalkoxy-lower carbonyl, or phenyloxycarbonyl.
The alkanoyl is primarily alkylcarbonyl, especially lower alkanoyl, for example acetyl. The N-mono- or N, N-disubstituted carbamoyl is especially substituted by one or two substituents independently selected from lower alkyl, phenylalkyl and lower hydroxyalkyl, or lower alkylene, lower oxaalkylene, or optionally substituted lower azaalkylene at the nitrogen atom terminal. A mono- or bicyclic heteroaryl group comprising zero, one, two or three nitrogen atoms in the ring and zero or one oxygen atom and zero or one sulfur atom, such groups in each case being unsubstituted or mono- or polysubstituted, refers to a heterocyclic moiety that is unsaturated in the ring that joins the heteroaryl radical to the moiety of the molecule in formula I and is preferably a ring, wherein in the binding ring, but optionally also in any annealed ring, so minus one carbon atom is replaced by a heteroatom selected from the group consisting of nitrogen, oxygen and sulfur; where the binding ring preferably has from 5 to 12, more preferably 5 or 6 atoms in the ring; and which may be unsubstituted or substituted by one or more, especially one or two, substituents selected from the group defined above as substituents for aryl, most preferably by lower alkyl, such as methyl, lower alkoxy, such as methoxy or ethoxy, or hydroxy . Preferably, the mono- or bicyclic heteroaryl group is selected from 2H-pyrrolyl, pyrrolyl, imidazolyl, benzimidazolyl, pyrazolyl, indazolyl, purinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 4H-quinolizinyl, isoquinolinyl, quinolinyl, phthalazinyl, naphthyridinyl, quinoxalyl. , quinazolinyl, quinolinyl, pteridinyl, indolizinyl, 3H-indolyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, furazanyl, benzo [d] pyrazolyl, thienyl and furanyl. More preferably the mono- or bicyclic heteroaryl group is selected from the group consisting of pyrrolyl, imidazolyl, such as 1 H-imidazol-1-yl, benzimidazolyl, such as 1-benzimidazolyl, indazolyl, especially 5-indazolyl, pyridyl, especially -, 3- or 4-pyridyl, pyrimidinyl, especially 2-pyrimidinyl, pyrazinyl, isoquinolinyl, especially 3-isoquinolinyl, quinolinyl, especially 4- or 8-quinolinyl, indolyl, especially 3-indolyl, thiazolyl, benzo [d] pyrazolyl, thienyl and furanyl. In a preferred embodiment of the invention, the pyridyl radical is substituted by hydroxy in the ortho position to the nitrogen atom and therefore exists at least partially in the form of the corresponding tautomer which is pyridin- (1 H) 2-one. In another preferred embodiment, the pyrimidinyl radical is substituted by hydroxy in both the 2 and 4 positions and therefore exists in various tautomeric forms, for example as pyrimidine- (1 H, 3 H) 2,4-dione. The heterocyclyl is especially a five, six or seven membered heterocyclic system with one or two heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, which may be unsaturated or fully or partially saturated, and is unsubstituted or substituted especially by lower alkyl , such as methyl, phenylalkyl-lower, such as benzyl, oxo, or heteroaryl, such as 2-piperazinyl; heterocyclyl is especially 2- or 3-pyrrolidinyl, 2-oxo-5-pyrrolidinyl, piperidinyl, N-benzyl-4-piperidinyl, N-alkyl-lower-piperazinyl, morpholinyl, for example 2- or 3-morpholinyl, 2-oxo -1 H-azepin-3-yl, 2-tetrahydrofuranyl, or 2-methyl-1,3-dioxolan-2-yl. The salts are especially the pharmaceutically acceptable salts of the compounds of the formula I. Such salts are formed, for example, as acid addition salts, preferably with organic or inorganic acids, from compounds of the formula I with an atom of basic nitrogen, especially pharmaceutically acceptable salts. Suitable inorganic acids are, for example, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organic acids are, for example, carboxylic, phosphonic, sulphonic or sulphamic acids, for example acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, amino acids, such as glutamic acid or aspartic acid, maleic acid, hydroxymalkeic acid, methylmaleic acid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, acid 4-aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, methano- or ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalene acid - disulfonic, 2-, 3- or 4-methylbenzenesulfuric acid, methylsulfuric acid, et ilsulfuric acid, dodecylsulfuric acid, N-cyclohexyl sulfamic acid, N-methyl-, N-ethyl- or N-propyl-sulfamic acid or other organic protonic acids, such as ascorbic acid. In the presence of negatively charged radicals, such as carboxy or sulfo, the salts can also be formed with bases, for example metal or ammonium salts, such as alkali metal or alkaline earth salts, for example sodium, potassium, magnesium salts or calcium, or ammonium salts with ammonia or suitable organic amines, such as tertiary monoamines, for example triethylamine or tri (2-hydroxyethyl) amine, or heterocyclic bases, for example N-ethyl-piperidine or N, N'-dimethylpiperazine. When a basic group and an acid group are present in the same molecule, a compound of the formula I can also form internal salts. For purposes of isolation or purification it is also possible to use pharmaceutically unacceptable salts, for example picrates or perchlorates. For therapeutic use, only pharmaceutically acceptable salts or compounds are used (when applicable in the form of pharmaceutical preparations) and therefore these are preferred. In view of the close relationship between the novel compounds in free form and those in the form of their salts, including those salts that can be used as intermediates, for example in the purification or identification of novel compounds, any reference to free compounds before and after the present is understood as a reference also to the corresponding salts, as appropriate and appropriate. The compounds within the scope of formula I and the process for their preparation are described in WO 04/005281 published January 15, 2004, which is incorporated in the present application by reference. A preferred compound is 4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [5- (4-methyl-1 H-imidazol-1-yl) -3- ( trifluoromethyl) phenyl] benzamide and pharmaceutically acceptable salts thereof of the formula (II):
In each case, when citations of patent applications or scientific publications are given, in particular for the pyrimidylaminobenzamide derivative compounds, the subject matter of the final products, the pharmaceutical preparations and the claims are incorporated in the present application by reference to these publications.
The structure of the active agents identified by code numbers, generic or brand names can be taken from the current edition of the standard "The Merck Index" compendium or from databases, for example Patents International (for example IMS World Publications). The corresponding content thereof is incorporated herein by reference. It has now been surprisingly found that the pyrimidylaminobenzamide derivatives have therapeutic properties, whereby they are particularly useful as an inhibitor of PDGFRa (platelet-derived growth factor a, also abbreviated as PDGFRa) and especially for the treatment or prophylaxis of diseases induced by FIP1 L1 -PDGFRa such as systemic mastocytosis. The FI P1 L1 -PDGFRa, as used before and after, is the designation of the fusion product of the FIP1 L1 genes (FIP1 as 1) with PDGFRa. The present invention thus relates to the use of pyrimidylaminobenzamide derivatives for the preparation of a drug for the treatment of systemic mastocytosis induced with FIP1 L1 -PDGFRα or similar mutations that activate PDGFRα. Systemic Mastocytosis (SM) includes indolent SM, aggressive MS, and non-mast cell disease of hematology and mast cell cell leukemia associated with MS. In another embodiment, the present invention relates to the use of pyrimidylaminobenzamide derivatives for the preparation of a pharmaceutical composition for use in the treatment of allergic rhinitis, allergic dermatitis, drug allergy or food allergy, angioedema, urticaria, infant death syndrome sudden, bronchopulmonary aspergillosis, multiple sclerosis, or mastocytosis, more particularly to treat allergic rhinitis, allergic dermatitis, allergy to drugs or food allergy, angioedema, urticaria, sudden infant death syndrome, bronchopulmonary aspergillosis, multiple sclerosis, or mastocytosis with resistance to imatinib. The term "allergic rhinitis" as used herein means any allergic reaction of the nasal mucosa. Such an allergic reaction can occur, for example, in a perennial manner, for example vernal conjunctivitis, or seasonally, for example, hay fever. The term "allergic dermatitis", as used herein, means especially atopic dermatitis, allergic contact dermatitis and eczematous dermatitis, but also includes, for example, seborrheic dermatitis, lichen planus, urticaria and acne. Atopic dermatitis, as defined herein, is a chronic inflammatory skin disorder seen in individuals with a hereditary predisposition to a decreased cutaneous threshold to pruritus. It is characterized mainly by excessive itching, which leads to scratching and rubbing which in turn results in the typical lesions of eczema. Allergic contact dermatitis, as defined herein, is a form of dermatitis is due to allergic sensitization to various substances which produces inflammatory reactions on the skin of those who have acquired hypersensitivity to the allergen as a result of prior exposure to East. The term "drug allergy or food allergy", as used herein, pertains to an allergic reaction caused by a drug or ingested antigens, such as, for example, strawberries, milk or eggs. Term "bronchopulmonary aspergillosis" refers to an infection of the lungs with Aspergillus. The term "mastocytosis", as used herein, refers to systemic mastocytosis, for example mast cell tumors, and also to neoplasms of canine mast cells. Mastocytosis is a myeloproliferative disorder with limited treatment options and generally a poor prognosis. The pathogenesis of mastocytosis has been attributed to the constitutive activation of receptor tyrosine kinase KIT. In a large majority of patients with mastocytosis, the deregulated KIT tyrosine kinase activity is due to a mutation within codon 816 of the protein (D816V) that also confers imatinib or imatinib mesylate, the latter being marketed as Gleevec® in the United States or Glivec® elsewhere, in vitro and in vivo. Mast cells play an important role as the major effector cells in the disorders mentioned herein. IgG-specific degranulation of mast cell antigen leads to the subsequent release of chemical mediators and multiple cytokines and synthesis of leukotriene. In addition, mast cells are involved in the pathogenesis of multiple sclerosis. Mast cell tumor neoplasms occur in both humans and animals. In dogs, the mast cell neoplasms are called mastocytomas, and the disease is common, accounting for 7% to 21% of canine tumors. A distinction should be made between human mastocytosis, which is usually transient or indolent, and canine mast cell neoplasm, which behaves unpredictably and is often aggressive and metastatic. For example, human solitary mast cells do not metastasize frequently; in contrast, 50% of canine mast cells behave in an evil way, as estimated by Hottendorf & Nielsen (1969) after reviewing 46 published reports of tumors in 938 dogs. Cancer in the pet population is a spontaneous disease. Pet owners, motivated by the extension of the quality of life of their animals, often seek the specialized care and treatment of veterinary oncologists in private veterinary hospitals and veterinary teaching hospitals throughout the country. The therapeutic modalities of cancer patients in veterinary medicine are similar to those of humans, including surgery, chemotherapy, radiation therapy and biotherapy. It has been estimated that there are 42 million dogs and approximately 20 million cats in the United States. Using approximate estimates of cancer incidence, there are approximately 4 million new cancer diagnoses made in dogs and a similar number in cats made each year. Cutaneous mast cell tumors in dogs are a common problem. Most of the mast cell tumors are benign and are cured with simple resection; however, if they are recurrent or metastatic in distant sites, the therapeutic options are limited. Treatment options for recurrent injuries may include external beam radiation therapy. For distant metastases or disseminated disease the use of Lomustine® and vinblastine containing chemotherapy protocols have shown some benefit. Sites for metastasis for mast cell tumors include skin, regional lymph nodes, spleen, liver and spinal cord. The involvement of KIT receptors in the pathogenesis of mastocytosis is suggested by the observation that several mutations that result in the constitutive activation of KIT have been detected in a number of mast cell lines. For example, a point of mutation in human c-KIT, which causes the replacement of Val by Asp81 6 in the phosphotransferase domain and receptor autoactivation, occurs in a long-term human mast cell line of leukemia (HMC-1) and in the corresponding codon in two rodent mast cell cell lines. In addition, this activation mutation has been identified in situ in some cases of human mastocytosis. Two other activation mutations have been found in the intracellular juxtamembrane region of KIT, namely the Val560Gly substitution in the human HMC-1 mast cell line, and an elimination of seven amino acids (Thr573-His579) in a mast cell line. of rodent called FMA3. The present invention relates more particularly to the use of pyrimidylaminobenzamide derivatives for the preparation of a drug for the treatment of systemic mastocytosis. In another embodiment, the present invention provides a method of treating systemic mastocytosis comprising administering to a mammal in need of such treatment, a therapeutically effective amount of pyrimidylaminobenzamide derivatives, or pharmaceutically acceptable salts or prodrugs thereof. Preferably, the present invention provides a method for treating mammals, especially humans, suffering from systemic mastocytosis which comprises administering to a mammal in need of such treatment an amount of inhibition of FIP1 L1 -PDGFRα of 4-methyl-3 - [[ 4- (3-pyridinyl) -2-pyrimidinyl] amino] -N- [5- (4-methyl-1 H -imidazol-1 -yl) -3- (trifluoromethyl) phenyl] benzamide (Compound (II)) or a pharmaceutically acceptable salt thereof. In the present description, the term "treatment" includes both prophylactic and preventive treatment, as well as curative or suppressive treatment of the disease, including treatment of patients at risk of contracting the disease or suspected of having contracted the disease as well as in sick patients. . This term also includes the treatment for delaying the progression of the disease.
The term "curative," as used herein, means efficacy in the treatment of ongoing episodes involving systemic mastocytosis. The term "prophylactic" means the prevention of the onset or recurrence of diseases that involve systemic mastocytosis.
The term "delay of progression", as used herein, means the administration of the active compound to patients who are in a pre-stage or in an early phase of the disease to be treated, in which patients are diagnosed. for example, of a pre-form of the corresponding nurse or in which the patients are in a condition, for example during a medical treatment or a condition resulting from an accident, under which a corresponding disease is likely to develop . This unpredictable range of properties means that the use of pyrimidylaminobenzamide derivatives is of particular interest for the preparation of a medicament for the treatment of systemic mastocytosis. This effect may be especially of clinical relevance for patients with systemic mastocytosis. To demonstrate that the pyrimidylaminobenzamide derivatives are particularly suitable for the treatment of systemic mastocytosis with good therapeutic margin and other advantages, clinical trials can be carried out in a manner known to the skilled person. The precise dosage of the pyrimidylaminobenzamide derivatives to be employed to inhibit systemic mastocytosis depends on several factors including the host, the nature and severity of the condition to be treated, the mode of administration. The compound of the formula I can be administered by any route including orally, parenterally, for example intraperitoneally, intravenously, intramuscularly, subcutaneously, intratumorally, or rectally, or enterally. Preferably the compound of formula I is administered orally, preferably in a daily dosage of 1 to 300 mg / kg of body weight or, for larger primates, a daily dosage of 50-5000, preferably 500 to 3000 mg . A preferred oral daily dosage is from 1 to 75 mg / kg of body weight or, for larger primates, a daily dosage of 10 to 2000 mg, administered as a single dose or divided into multiple doses, such as a daily dosage of two. times. Usually, a small dose is initially administered and the dosage is gradually increased until the optimal dosage for the host under treatment is determined. The upper limit of dosage is that imposed by side effects and can be determined by assay for the host being treated. The compounds of the formula I can be combined with one or more pharmaceutically acceptable carriers and, optionally, one or more conventional pharmaceutical auxiliaries and administered enterally, for example orally, in the form of tablets, capsules, etc., or parenterally. , for example intraperitoneally or intravenously, in the form of sterile injectable solutions or suspensions. The enteric and parenteral compositions can be prepared by conventional means. The pyrimidylaminobenzamide derivatives can be used alone or in combination with at least one other pharmaceutically active compound for use in these pathologies. These active compounds can be combined in the same pharmaceutical preparation or in the form of a "package of parts" of combined preparations in the sense that the combination of components can be dosed independently or by using different fixed combinations in different amounts of the components of the combination, that is, simultaneously or at different times. The parts of the package of parts can then be administered, for example, or staggered chronologically, ie at different times and with equal or different time intervals for any part of the package of parts. Non-limiting examples of compounds that may be cited for use in combination with pyrimidylaminobenzamide derivatives are cytotoxic chemotherapy drugs, such as cytosine arabinoside, daunorubicin, doxorubicin, cyclophosphamide, VP-16, or imatinib, etc. In addition, the pyrimidylaminobenzamide derivatives could be combined with other inhibitors of signal transduction or other drugs labeled oncogene with the expectation that a significant synergy would result. The invention further pertains to the combination of a pyrimidylaminobenzamide derivative as described hereinabove with imatinib for the treatment of the diseases and conditions described hereinbefore. The administration of such a combination can be carried out at the same time, for example in the form of a combination or combined pharmaceutical preparation, fixed, or sequentially or staggered in moments. The administration of a pyrimidylaminobenzamide derivative in a dosage form as described hereinabove and imatinib in its marketed form of Gleevec® in the EU / Glivec® in Europe and with dosages designed for these dosage forms is currently preferred . The treatment of systemic mastocytosis with the above combination may be a first-line treatment, that is, the treatment of a newly diagnosed disease without any preceding chemotherapy or the like, or it may also be a so-called second line treatment, that is, the treatment of the disease after a preceding treatment with imatinib or a pyrimidylaminobenzamide derivative, depending on the severity or stage of the disease as well as the overall condition of the patient, etc. The efficacy of the pyrimidylaminobenzamide derivatives for the treatment of systemic mastocytosis is illustrated by the results of the following examples. These examples illustrate the invention without limiting its scope in any way: IL-3 cell independence proliferation assays: The effects of the compounds on the viability and proliferation of the cells are determined using the ATPLite luminescent ATP detection assay package. Perkin Elmer Life Sciences ™ (Cat. No: 601 6947) according to the instructions of the suppliers. This test system is based on the production of light (luminescence) caused by the reaction of ATP with luciferase and D-luciferin aggregates. Cell lines of Ba / F3 FIP-PDGFRa, package D-816-V of Ba / F3, package D-81 6-Y of Ba / F3, package of the VV of Ba / F3, package R-634-W of Ba / F3 , cultured in suspension in RPM 1 640 (Invitromex, Cat. No.: L0501), 10% fetal calf serum (Amimed, Cat. No.: 2-01 F86-I), 2 mM L-glutamine (Gibco) , are plated in tissue culture plates of 96 black wells (Packard) at a density of 10,000 cells per well in 50 μl of complete medium followed immediately by the addition of 50 μL per well of dilution of two times serial of concentrated 2x compounds (duplicates). The cells without compound are used as a control and the cell-free medium is used to determine the background signal of the assay. After incubation for 70 h (37 ° C, 5% CO2), the cells are lysed by addition of 50 μL per well of mammalian cell lysis solution (provided with the package) and 5 min of agitation in a shaker. orbital plate at 700 rpm. Subsequently, 50 μL of substrate solution (luciferase and D-luciferin) are added and after 5 min of stirring and 10 min of adaptation to the dark of the plates, the light emission is measured with a Packard TopCount. The activity of the compound is determined as the inhibition of total growth (TG I) of the cell cultures and is calculated as follows: after subtraction of the background signal the signal obtained for the control cells is taken as 100%. The effect of the compound is expressed as percent reduction of the control signal. The TGI50 values are determined from the dose response curves by graph extrapolation. GIST882 is a human gastrointestinal stromal tumor (GIST) cell line expressing a KIT mutation activity (exon 1 3, K-642-E) (Tuveson DA, Willis NA, Jacks, T. Griffin JD, Singer S, Fletcher CD, Fletcher JA, Demetri GD, inactivation of STI571 of the oncoprotein c-KIT of gastrointestinal stromal tumor: biological implications and clinical trials Oncogen, August 2001 1 6; 20 (36): 5054-8). GIST882 cells are grown in RPM l 1640 (Invitrome ?, Cat. No.: L0501), supplemented with 5% FCS and 2 mM glutamine (Gibco). Cell culture flasks and 96-well tissue culture plates are treated with 1.5% gelatin solution in nanopure water for 30 to 60 min at 37 ° C before seeding the cells to improve adherence and growth of the cells. cells The gelatin (BIORAD, purity reagent EIA, # 1 70-6537) is sterilized before use by heating (autoclave). The IST882 G cells are seeded in 96-well black plates (Packard) for tissue culture at a density of 1 0000 cells per well in 5 μL of complete medium and incubated for one day in order to allow the binding of the cells Serial two-fold dilutions of concentrated compound 2? they are added (50 μL per well) in duplicates (final volume: 1 00 μL per well). The cells without compound are used as a control and the cell-free medium is used to determine the background signal of the assay. After 70 h of incubation (37 ° C, 5% CO2), the cells are lysed by addition of 50 μL per well of mammalian cell lysis solution (provided with the package) and 5 min of agitation on a shaker of orbital plate at 700 rpm. Subsequently, 50 μL of substrate solution (luciferase and D-luciferin) are added and after 5 min of agitation and 10 min of adaptation to the dark of the plates, the light emission was measured with a TopCount Packard. The activity of the compound is determined as total growth inhibition (TGI) of the cell cultures and is calculated as follows: after subtraction of the background signal the signal obtained for the control cells is taken as 1 00%. The effect of the compound is expressed as percent reduction of the control signal. The TG I50 values are determined from the dose response curves by graphical extrapolation. The compound (II) inhibits the proliferation of IST882 G cells with an average value of I C50 of < 200 nM. Assay to determine the effects of Kit autophosphorylation on cells: The phosphorylation status of cell targets on lysates from cells - untreated or compound treated - is determined with capture ELISAs. The adherent cells are grown in 96-well flat bottom tissue culture plates near the confluence. Cells growing in suspension are seeded at 100000 - 150000 cells per well. After treatment with serial dilutions of compound the cells are washed once with PBS followed by lysis of cells with 100 to 150 μL of lysis buffer (50 mM Tris / HCl, pH 7.4, 150 mM sodium chloride, 150 mM EDTA, 1 mM EGTA, 1% NP-40, 2 mM sodium orthovanadate, 1 mM PMSF, 50 μg / mL aprotinin and 80 μg / mL leupeptin). The cell lysates are used immediately or stored at 20 ° C. 50 μL of the lysates are transferred to black ELISA plates (NUNC-Msxisorp, Cat. No .: No. 437111) which are pre-coated with an anti-CD117 antibody. monoclonal obtained from Diaclone (# 854,510,000) are used. For coating, the antibody is diluted in PBS and incubated with the plates overnight at 4 ° C (50 μL / well). The phosphorylation of the captured kit is detected using a commercial anti-P-Tyr Ab, labeled with alkaline phosphatase (AP), PY20 AP of Zymed, in a final concentration range between 1: 3000 and 1: 10000 (0.1 to 0.33 μg / ml). The second Ab is added after the removal of the cell lysates. Finally, add 90 μL per well of a chemiluminescent AP substrate (CDPStar RTU with Emerald II from Applied Biosistems (Cat. No .: T2388C) and incubate for 45 min at RT in the dark.The plates are sealed with plate sealer Packard TopSeaITM-A (Cat. No. 6005185) and the luminescence is quantified by measuring the counts per second (CPS) with a Packard TopCount Microplate Scintillation Counter (Top Count) The difference between the ELISA reading (CPS) obtained with the Used of untreated cells and the reading to the bottom of the assay (all components, but without the cell lysate) is calculated and taken as 100% reflecting the phosphorylated Kit protein constitutively present in these cells. The activity of the compound in the kinase activity of Kit is expressed as a percentage of reduction of Kit phosphorylation. The values for the IC50 and IC90 are determined from the dose response curves by graphical extrapolation. Example I An open label, Phase II study was designed to evaluate the safety and efficacy of Compound (II) orally administered 400 mg twice daily. Patients with MS who meet the specific disease criteria and with a clinical indication for treatment were enrolled. Results are based on preliminary information for the first 23 pts in this study. Results: the average age was 49 (range of 33 to 78) years and the mean time from the diagnosis of MS was 27 (range of 1 to 292) months. For those with available information, 13/17 pts had a c-kit D816V mutation in spinal cord cells. The average position to compound (II) was 144 days. The treatment is carried out for 18 (78%) pts; 5 (22%) discontinuous, 3 (13%) for adverse events and 2 (9%) withdrew consent. Three (13%) responses were reported (2 incomplete remission and 1 minor response), based on serum tryptase, mast cell counts of the spinal cord and improvement of clinical symptoms. Baseline mutation information is available for 2 of the 3 pts of response and reveals the mutation of c-kit D816V. These data suggest that Compound (I I) has clinical activity and an acceptable safety and tolerance profile in sts with SM.